posted on 2023-04-03, 23:24authored byJessica Michie, Paul A. Beavis, Andrew J. Freeman, Stephin J. Vervoort, Kelly M. Ramsbottom, Vignesh Narasimhan, Emily J. Lelliott, Najoua Lalaoui, Robert G. Ramsay, Ricky W. Johnstone, John Silke, Phillip K. Darcy, Ilia Voskoboinik, Conor J. Kearney, Jane Oliaro
Movie S2
Funding
National Nature Science Foundation of China
History
ARTICLE ABSTRACT
Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the “inhibitor of apoptosis proteins” with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T-cell–derived TNF. Combining CAR T-cell therapy with birinapant significantly reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrated the synergistic potential of combining CAR T-cell therapy with smac-mimetics. Taken together, we identified CAR T-cell–derived TNF as a potent antitumor effector, which can be further harnessed by smac-mimetics.